The biochemical, physiological, and clinical effects of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major CGMP hydrolyzing lyzing enzyme in vascular smooth muscle, and its expression in penile corpus cavernosum has been reported (Taher et al., J. Urol., 149, p. 285A (1993)). Thus, PDES is an attractive target in the treatment of sexual dysfunction (Murray, DN&P 6(3), pp. 150-56 (1993)).
A pharmaceutical product, which provides a PDE5 inhibitor, is currently available and marketed under the trademark VIAGRA®. The active ingredient in VIAGRA® is sildenafil. The product is sold as an article of manufacture including 25, 50, and 100 mg tablets of sildenafil and a package insert. The package insert provides that sildenafil is a more potent inhibitor of PDE5 than other known phosphodiesterases (greater than 80 fold for PDEl inhibition, greater than 1,000 fold for PDE2, PDE3, and PDE4 inhibition). The IC50 for sildenafil against PDE5 has been reported as 3 rM (Drugs of the Future, 22(2), pp. 138-143 (1997)) and as 3.9 nM (Boolel et al., Int. J. of Impotence, 8, pp. 47-52 (1996)). Sildenafil is described as having a 4,000-fold selectivity for PDE5 versus PDE3, and only a 10-fold selectivity for PDE5 versus PDE6. Its relative lack of selectivity for PDE6 is theorized to be the basis for abnormalities related to color vision.
While sildenafil has obtained significant commercial success, it has fallen short due to its significant adverse side effects, including facial flushing (10% incidence rate). Adverse side effects limit the use of sildenafil in patients suffering from vison abnormalities, hypertension, and, most significantly, by individuals who use organic nitrates (Welds et al., Amer. J. of Cardiology, 83(5A), pp. 21(C)-28(C) (1999)).
The use of sildenafil in patients taking organic nitrates causes a clinically significant drop in blood pressure which could place the patient in danger. Accordingly, the package label for sildenafil provides strict contraindications against its use in combination with organic nitrates (e.g., nitroglycerin, isosorbide mononitrate, isosorbide nitrate, erythrityl tetranitrate) and other nitric oxide donors in any form, either regularly or intermittently, because sildenafil potentiates the hypotensive effects of nitrates. See C. R. Conti et al., Amer. J. of Cardiology, 83(5A), pp. 29C-34C (1999). Thus, even with the availability of sildenafil, there remains a need to identify improved pharmaceutical products that are useful in treating sexual dysfunction.
Daugan U.S. Pat. No. 5,859,006 discloses certain tetracyclic derivatives that are potent inhibitors of cGMP-specific PDE, or PDES. The IC50 of the compounds disclosed in U.S. Pat. No. 5,859,006 is reported in the range of 1 nM to 10 μM. The oral dosage for such compounds is 0.58 mg daily for an average adult patient (70 kg). Thus, unit dosage forms (tablets or capsules) are reported as 0.2 to 400 mg of active compound. Significant adverse side effects attributed to compounds disclosed in U.S. Pat. No. 5,859,006 are not disclosed.
Applicants have discovered that one such tetracyclic derivative, (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione, alternatively named (6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino-[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, and referred to herein as Compound (I), can be administered in a unit dose that provides an effective treatment without the side effects associated with the presently marketed PDE5 inhibitor, sildenafil. Prior to the present invention such side effects were considered inherent to the inhibition of PDE5.
Significantly, applicants' clinical studies also reveal that an effective product having a reduced tendency to cause flushing in susceptible individuals can be provided. Most unexpectedly, the in product also can be administered with clinically insignificant side effects associated with the combined effects of a PDE5 inhibitor and an organic nitrate. Thus, the contraindication once believed necessary for a product containing a PDE5 inhibitor is unnecessary when Compound (I) is administered as a unit dose of about 1 to about 20 mg, as disclosed herein. Thus, the present invention provides an effective therapy for-sexual dysfunction in individuals who previously were untreatable or suffered from unacceptable side effects, including individuals having cardiovascular disease, such as in individuals requiring nitrate therapy, having suffered a myocardial infarction more than three months before the onset of sexual dysfunction therapy, and suffering from class 1 congestive heart failure, or individuals suffering from vision abnormalties.
The present invention provides Compound (I) in a unit dosage form. That is, the present invention provides a pharmaceutical unit dosage form suitable for oral administration comprising about 1 to about 20 mg Compound (I).